PROJECT SUMMARY Extensive research ties mitochondria to Alzheimer's disease (AD), but how mitochondria contribute to AD risk or progression remains unsettled. Here, we build on new and compelling data that indicate the mitochondrial DNA (mtDNA) haplogroup J occurs in higher frequencies in persons with AD. This finding argues mitochondria independently contribute to AD, and is particularly unexpected as increased haplogroup J frequency paradoxically also occurs in the oldest old. Four specific haplogroup J-defining polymorphisms appear to drive the association; three reside in the mtDNA control region that regulates mtDNA replication and transcription, and the fourth is a non-synonymous ND5 variant. These variants travel together and currently we cannot tell whether the control region variants, the protein-coding variant, or a combination contributes to AD risk. To resolve this and gain new AD mechanistic insight, we propose a synergistic two-aim, bench-and- bedside approach that will extend these genetic associations to functional associations. In Aim 1, we use cytoplasmic hybrid (cybrid) cell lines to define how the haplogroup J variants affect mitochondrial function and integrity. In Aim 2, we use clinical biospecimen and biomarker data to further explore the haplogroup J, AD, and aging nexus. Thus, in addition to advancing our understanding of AD, our mechanistic analysis of haplogroup J effects will also inform how mitochondrial biology relates to aging. These studies will provide insight into mechanisms that cause AD and aging to converge, but also occasionally diverge.